Noradrenergic (NA) neurons have been implicated in a variety of brain functions and in several neuropsychiatric disorders, especially depression. The goal of this proposal is to provide a detailed account of the organization of descending projections from NA cells to spinal cord and brainstem. The central theme of the proposal is that NA cells in the rat brainstem are functionally not homogeneous but that subgroups can be distinguished based upon their efferent and afferent connections. Specifically, we propose to test the hypothesis that the dorsal horn of the spinal cord and sensory nuclei of the brainstem are innervated by NA cells of the locus coeruleus and subcoeruleus and that motoneurons of the spinal cord and brainstem are innervated by NA cells of the A5 and A7 groups. Three sets of experiments are proposed to demonstrate that NA cells of the LC, the A5 and the A7 groups have different efferent and afferent connections: (1) We will identify the NA cells that innervate sensory nuclei and those that innervate motor nuclei of the brainstem using retrograde transport of the fluorescent tracer True Blue in combination with dopamine-beta-hydroxylase immunocytochemistry for histochemical identification of NA cells. (2) We will determine the sites of termination of NA projections of the LC, A5 and A7 groups in spinal cord and brainstem using anterograde transport of PHA-L. 3) We will determine whether NA cells of the LC, the A5 and A7 groups receive different afferents using retrograde transport of HRP conjugated to wheat germ agglutinin as tracer. The results of this study will provide an accurate description of the origin and termination of descending NA pathways. This will make it possible to identify NA subgroups with different projections to the spinal cord and brainstem, and will allow us to assign specific functions to each of these subgroups. The characterization of the functional organization of descending NA projections will be of considerable clinical importance since a large number of widely prescribed drugs affect the activity of NA neurons.